title: Deletion of WNK1 first intron results in misregulation of both isoforms in renal and extrarenal tissues.
abstract: Large deletions in intron 1 of the with-no-lysine kinase type 1 (WNK1) gene cause familial hyperkalemic hypertension. Alternative promoters generate functionally different isoforms: long ubiquitous isoforms (L-WNK1) and a kidney-specific isoform (KS-WNK1) lacking kinase activity. It remains unclear whether the disease-causing mutations selectively modify the synthesis of 1 or both types of isoforms. Using a transgenic mouse model, we found that intron 1 deletion resulted in the overexpression of L- and KS-WNK1 in the distal convoluted tubule and ubiquitous ectopic KS-WNK1 expression. Phylogenetic and functional analysis of the minimal 22-kb intron 1 deletion identified 1 repressor and 1 insulator, potentially preventing interactions between the regulatory elements of L-WNK1 and KS-WNK1. These results provide the first insight into the molecular mechanisms of WNK1-induced familial hyperkalemic hypertension.
authors.affiliation: Faculté de Médecine, Université Paris Descartes Paris V, Collège de France, INSERM Unit 772, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Delaloy
authors.forename: Emilie
authors.initials: E
authors.lastname: Elvira-Matelot
authors.forename: Maud
authors.initials: M
authors.lastname: Clemessy
authors.forename: Xiao-ou
authors.initials: XO
authors.lastname: Zhou
authors.forename: Martine
authors.initials: M
authors.lastname: Imbert-Teboul
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Houot
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Juliette
authors.initials: J
authors.lastname: Hadchouel
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004285:Dogs; D053595:Embryonic Stem Cells / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D017930:Genes, Reporter; D006801:Humans; D006947:Hyperkalemia / Q000235:genetics* / Q000503:physiopathology; D006977:Hypertension, Renal / Q000235:genetics* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns / Q000235:genetics; D007668:Kidney / Q000166:cytology / Q000502:physiology*; D007962:Leukocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D018482:Muscle, Skeletal / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human